Abstract The ability to intervene during the risk phase of dementia is paramount in reducing the conversion to dementia- related illnesses and improving long-term outcomes. There is emerging evidence that simultaneously combining physical activities with cognitive tasks leverages neuroplasticity and results in greater cognitive benefits than either of them alone. The proposed R21 project will translate our highly innovative clinic- based simultaneous aerobic exercise and memory skills training (SIM) program into a mobile-based web application for wider dissemination to improve memory functioning in MCI patients. We will first develop and beta test the mobile SIM (mSIM) program at home in 5 amnestic mild cognitive impairment (aMCI; single-domain, primary memory loss) patients over 12-weeks (2 sessions/week, 70 minutes/session) to test feasibility and refine the mSIM program. Each mSIM session will include 20 minutes of sedentary new memory skills introduction and learning through the internet-enabled tablet application, 5 minute aerobic warm-up on the bike (50% Heart Rate Reserve), 40 minutes of memory skills training and practice using our tablet application while aerobic cycling (65-80% HRR), then a 5 minute cool- down. We will conduct a pilot, 12-week RCT by randomly assigning 30 aMCI patients (ages 65-80) to either the mSIM condition (N=15) or an activity monitoring only (via FitBit) control (CON) group (N=15), to study the effects of the mSIM intervention on memory performance and everyday functioning compared to an observational control group. These findings will be used as pilot data for a well- powered NIA R01 clinical trial grant. Elevations in both endogenous levels of brain derived neurotrophic factor (BDNF) and norepinephrine (NE) have been found in response to exercise interventions and were also related to memory improvements in MCI patients. To explore the underlying neurobiological mechanisms of the novel mSIM intervention we will collect peripheral biomarkers of BDNF and NE at baseline and post-intervention. The proposed research will address the following questions: 1. Is a 12 week (2x/week 70 minute) mSIM home-based, technology-enhanced intervention feasible for older adults with aMCI? 2. Does the mSIM intervention improve memory and everyday functioning? 3. Are there increases in underlying exercise-induced neurobiological mechanisms: peripheral BDNF (collected via blood serum) and norepinephrine levels (collected via saliva)? 4. Are elevations in the biomarkers related to improvements in memory functioning?